Discovery of novel HCV inhibitors: Synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B

Zhang, Xiaoyan; Zhang, Nanjing; Chen, Guangming; Turpoff, Anthony; Ren, Hongyu; Takasugi, James; Morrill, Christie; Zhu, Jin; Li, Chunshi; Lennox, William; Paget, Steven D.; Liu, Yalei; Almstead, Neil G.; Njoroge, F. George; Gu, Zhengxian; Komatsu, Takashi; Clausen, Valerie A.; Espiritu, Christine; Graci, Jason D.; Colacino, Joseph M.; Lahser, Frederick; Risher, Nicole; Weetall, Marla; Nomeir, Amin A.; Karp, Gary M.

doi:10.1016/j.bmcl.2013.04.049

Cited by 30 publications

(42 citation statements)

References 22 publications

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“…Despite a fairly thorough chemistry effort (Ͼ200 compounds synthesized), we were unable to find compounds that were more potent than the ones described against HCV 1b or that had a relative improvement of potency against genotype 1a or 2a. Reports from other chemical series have shown a similar loss of potency against genotype 2a (6,8,9,13,14), although in the case of Phillips et al (14), while the potency against genotype 2a shifted about 30-fold compared with that against genotype 1b, it was still in the low nanomolar range.…”

Section: Discussionmentioning

confidence: 78%

“…While this series is chemically distinct from previously reported series (6-9, 12-14), GSK0109 and GSK4809 appear to interact at a similar site on NS4B, although they give a partially different resistance profile in tissue culture. Notably, these compounds are not sensitive to amino acid substitutions at H94 and V105 in the genotype 1b replicon, which has been observed with inhibitors targeting NS4B (7)(8)(9).…”

Section: Discussionmentioning

confidence: 82%

“…Other classes of DAAs showing clinical efficacy target the NS5A protein (3,4) or viral polymerase (NS5B; reviewed in reference 5). Of the other viral proteins, several smallmolecule DAAs to nonstructural protein NS4B have been identified (6)(7)(8)(9)(10)(11)(12)(13)(14), but to date, there are no examples of clinically active NS4B-targeting compounds.…”

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confidence: 99%

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Encoded Library Technology Screening of Hepatitis C Virus NS4B Yields a Small-Molecule Compound Series with In Vitro Replicon Activity

Zhu

Dickson

Parks

et al. 2015

Antimicrob Agents Chemother

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To identify novel antivirals to the hepatitis C virus (HCV) NS4B protein, we utilized encoded library technology (ELT), which enables purified proteins not amenable to standard biochemical screening methods to be tested against large combinatorial libraries in a short period of time. We tested NS4B against several DNA-encoded combinatorial libraries (DEL) and identified a single DEL feature that was subsequently progressed to off-DNA synthesis. The most active of the initial synthesized compounds had 50% inhibitory concentrations (IC 50 s) of 50 to 130 nM in a NS4B radioligand binding assay and 300 to 500 nM in an HCV replicon assay. Chemical optimization yielded compounds with potencies as low as 20 nM in an HCV genotype 1b replicon assay, 500 nM against genotype 1a, and 5 M against genotype 2a. Through testing against other genotypes and genotype 2a-1b chimeric replicons and from resistance passage using the genotype 1b replicon, we confirmed that these compounds were acting on the proposed first transmembrane region of NS4B. A single sequence change (F98L) was identified as responsible for resistance, and it was thought to largely explain the relative lack of potency of this series against genotype 2a. Unlike other published series that appear to interact with this region, we did not observe sensitivity to amino acid substitutions at positions 94 and 105. The discovery of this novel compound series highlights ELT as a valuable approach for identifying direct-acting antivirals to nonenzymatic targets. Significant progress has been made in recent years in the discovery and development of novel direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) infection. However, the ability of HCV to rapidly evolve and develop resistance is such that there is a continued need to discover DAAs that act through novel mechanisms. The standard of care for chronic HCV infection was a combination of pegylated alpha interferon and ribavirin up until the approval of the NS3 protease inhibitors telaprevir and boceprevir in 2011 (1, 2). Other classes of DAAs showing clinical efficacy target the NS5A protein (3, 4) or viral polymerase (NS5B; reviewed in reference 5). Of the other viral proteins, several smallmolecule DAAs to nonstructural protein NS4B have been identified (6-14), but to date, there are no examples of clinically active NS4B-targeting compounds.NS4B is a small (27-kDa), hydrophobic, membrane-associated protein that is derived through processing of the HCV polyprotein by the viral protease NS3/4A (reviewed in references 15, 16, and 17). It complexes with other HCV nonstructural and possibly a host cell factor(s) to form the viral replicase (18-22), which serves to replicate the viral RNA and is likely coupled to the assembly process (20, 23). Besides its structural role in the replicase, NS4B is thought to be involved in the induction of membranous vesicles that provide a platform for HCV RNA replication (24, 25), and it may also participate in virion assembly and release (26,27). NS4B is also reported to hydr...

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 82%

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Encoded Library Technology Screening of Hepatitis C Virus NS4B Yields a Small-Molecule Compound Series with In Vitro Replicon Activity

Zhu

Dickson

Parks

et al. 2015

Antimicrob Agents Chemother

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“…113 In addition, 52 showed a significant improvement of the in vitro metabolic stability, measured as HML clearance. It was also observed that a different regiochemistry of the heteroaryl ring (53) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 In the same study, the authors explored the chemical space of the 6-(indol-2-yl)pyridine-3-sulfonamide class by preparing a large number of analogues modified at N-1, C-5, and C-6 of the indole core as well as at the sulfonamide group.…”

Section: ) With Hit Compound 52mentioning

confidence: 98%

“…113 The chemical modifications pointed to overcome the issues related to 51 such as poor aqueous solubility, high HLM metabolic liability, and production of the inactive N-sulfonamido dealkylated metabolite when orally administered in rats. In response to these issues, Zhang et al investigated a small set of sulfonamides, close analogues of compound 51, by replacing the C-2 phenyl ring with nitrogencontaining heteroaryl rings.…”

Section: Figure 18 Structures and Activities Of Selected N-(4'-(indomentioning

confidence: 99%

A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

et al. 2015

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Hepatitis C virus (HCV) infection is a global health burden with an estimated 130-170 million chronically infected individuals and is the cause of serious liver diseases such as cirrhosis and hepatocellular carcinoma. HCV NS4B protein represents a validated target for the identification of new drugs to be added to the combination regimen recently approved. During the last years, NS4B has thus been the object of impressive medicinal chemistry efforts, which led to the identification of promising preclinical candidates. In this context, the present review aims to discuss research published on NS4B functional inhibitors focusing the attention on hit identification, hit-to-lead optimization, ADME profile evaluation, and the structure-activity relationship data raised for each compound family taken into account. The information delivered in this review will be a useful and valuable tool for those medicinal chemists dealing with research programs focused on NS4B and aimed at the identification of innovative anti-HCV compounds.

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2‐(Hetero)Arylindoles

2018

Privileged Structures in Drug Discovery

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Discovery of novel HCV inhibitors: Synthesis and biological activity of 6-(indol-2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B

Cited by 30 publications

References 22 publications

Encoded Library Technology Screening of Hepatitis C Virus NS4B Yields a Small-Molecule Compound Series with In Vitro Replicon Activity

Encoded Library Technology Screening of Hepatitis C Virus NS4B Yields a Small-Molecule Compound Series with In Vitro Replicon Activity

A Journey around the Medicinal Chemistry of Hepatitis C Virus Inhibitors Targeting NS4B: From Target to Preclinical Drug Candidates

2‐(Hetero)Arylindoles

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